JP7340602B2 - Continuous flow reactor for virus inactivation - Google Patents

Description

TECHNICAL FIELD This disclosure generally relates to apparatus and processes for continuous flow reactors. More particularly, the present disclosure provides an apparatus for a continuous flow reactor having at least two turns on a single longitudinal axis, each turn disposed in a different non-parallel plane. and process related.

The present invention is in the field of the production of biological products, such as proteins, which is typically carried out in bioreactors (fermenters) in which eukaryotic cells are cultured to produce the protein of interest. Therefore, various techniques are established, for example fed-batch or continuous or perfusion fermentation. Before use, the product needs to be purified. Among the purification steps, inactivation of the virus is essential, especially if the product is intended for human use.

Currently, virus inactivation at low pH is performed in batch reactors. The material to be inactivated (ie, the liquid potentially containing active virus) is introduced into a batch reactor. The material to be inactivated is brought to pH≦4 with an acidic solution and left for the required time. Inactivation of the virus is accomplished by contacting the virus with an acidic solution for a period of time that depends on the particular product and process. The entire contents of the batch reactor are inactivated with substantially the same residence time. Furthermore, the virus reduction achieved within each batch is substantially the same.

In one aspect, a continuous flow reactor is provided. A continuous flow reactor includes a plurality of interwoven flow passages in fluid communication to form a single continuous flow reactor tube having a single flow passage.

In another aspect, each of the plurality of interwoven channels includes a plurality of turns in different non-parallel planes.

In a further aspect, the plurality of turns includes at least a first pattern and a second pattern different from the first pattern, the first pattern includes a predetermined number of turns, and the second pattern includes a predetermined number of turns. The predetermined number of turns in the first pattern is the same as or different from the predetermined number of turns in the second pattern.

In one aspect, the plurality of turns includes a repeating pattern of turns.

In another aspect, the pattern of turns is repeated after eight bends.

In a further aspect, each of the plurality of turns includes an angle of about 100° to about 200°.

In one aspect, each of the plurality of turns includes an angle of about 135° to about 140°.

In another aspect, the plurality of turns follow a three-dimensional path that includes a flow direction that varies by about 45° at the center of the turn.

In a further aspect, the plurality of interwoven channels are made from at least one of a flexible alloy and a memory alloy.

In one aspect, the plurality of interwoven channels includes from about 19.6 to about 39.2 turns ^{per cubic} meter.

In another aspect, the plurality of interwoven channels include internals.

In a further aspect, the plurality of interwoven channels includes a weft-like pattern and a warp-like pattern.

In one aspect, the plurality of interwoven channels includes a plurality of bends, each bend being rotated relative to one another at an angle about a longitudinal axis of the plurality of interwoven channels.

In another aspect, the angle of the interwoven channels about the longitudinal axis is about 25 degrees to about 60 degrees.

In one aspect, a continuous flow reactor is provided. A continuous flow reactor includes at least one flow path on a single longitudinal axis and includes a plurality of turns, at least two of the plurality of turns in different non-parallel planes.

In another aspect, the plurality of turns includes a first pattern that is repeated a predetermined number of times.

In a further aspect, the plurality of turns includes at least a first pattern and a second pattern different from the first pattern, the first pattern includes a predetermined number of turns, and the second pattern includes a predetermined number of turns. The predetermined number of turns in the first pattern is the same as or different from the predetermined number of turns in the second pattern.

In one aspect, each of the plurality of turns is separated from each other by a bend having an angle less than the angle of the plurality of turns.

In another aspect, each of the bends includes an angle of less than about 135° and each of the plurality of turns includes an angle of about 135° to about 140°.

In a further aspect, the at least one channel includes four channels interwoven with each other.

In one aspect, a method of virus inactivation in a continuous flow reactor is provided. The method includes a process stream to a continuous flow reactor at a flow rate having a Reynolds number of about 187 to about 333 and a Dean number of about 105 to about 212, and at least one virus inactivating compound or solution; contacting the process stream with at least one virus-inactivating compound or solution within.

In another aspect, a process is provided for continuous low pH of virus inactivation of a product stream.

Additional features and advantages of the various embodiments are set forth in part in the description that follows, and in part may be obvious from the description, or may be learned by practice of the various embodiments. The objects and other advantages of the various embodiments will be realized and attained by the elements and combinations particularly pointed out in the description.

The present disclosure, in its several aspects and implementations, may be more fully understood from the detailed description and accompanying drawings.

1 is a perspective view of a continuous flow reactor showing its casing and exemplary reactor tubes, according to an example of the present disclosure; FIG. 1A is a partial perspective view of the continuous tube reactor of FIG. 1A, according to an example of the present disclosure; FIG. 1B is a rear view of the continuous tube reactor of FIG. 1A, according to an example of the present disclosure. FIG. 1A illustrates a perspective, front, and side view of the continuous flow reactor of FIG. 1A, according to an example of the present disclosure. FIG. 1 is an isometric view of an exemplary continuous flow reactor tube with a single run, according to an example of the present disclosure; FIG. 2A illustrates the continuous flow reactor tube of FIG. 2A with turns on a single longitudinal axis but in different non-parallel planes, according to an example of the present disclosure; FIG. 2A is a top view of the example continuous flow tube of FIG. 2A, according to an example of the present disclosure; FIG. 2B is a cross-sectional view along the longitudinal access of the tube of FIG. 2A, according to an example of the present disclosure; FIG. FIG. 2A is the continuous flow reactor tube of FIG. 2A having a first flow path with turns and a second substantially straight path, according to an example of the present disclosure. 2A is a side view of the exemplary continuous flow tube of FIG. 2A, according to an example of the present disclosure. FIG. 2F is a detail view of area A of the side view of the exemplary continuous flow tube of FIG. 2F, according to an example of the present disclosure; FIG. 1 is an isometric view of an exemplary continuous flow tube with four runs, according to an example of the present disclosure; FIG. 3B is a top view of the example continuous flow tube of FIG. 3A, according to an example of the present disclosure. FIG. 3B is a bottom view of the example continuous flow tube of FIG. 3A, according to an example of the present disclosure. FIG. 3B is a detailed view of a connection point between a first flow path and a second flow path of the exemplary continuous flow tube of FIG. 3A, according to an example of the present disclosure; FIG. FIG. 3 illustrates a first flow path and a second flow path having a weft-like pattern, according to an example of the present disclosure. FIG. 3 illustrates a first flow path and a second flow path having a warp-like pattern, according to an example of the present disclosure; FIG. 2 illustrates a first flow path having a warp-like pattern and a second flow path having a weft-like pattern, according to an example of the present disclosure. 2 illustrates a plurality of continuous flow reactors connected to each other, according to an example of the present disclosure. FIG. 6 shows centerline velocity of the woven channel for an inlet velocity of 5.26E-02 m s ⁻¹ according to an example of the present disclosure; FIG. 3 illustrates a flow path and axial velocity profile along a woven flow path according to an example of the present disclosure. 8 illustrates details of the weave design planar velocity profile and Dean vortex/radial velocity of FIG. 7, according to an example of the present disclosure; FIG. 9 shows maximum velocities calculated using an inlet velocity of 5.26E-01 m s ⁻¹ estimated for each of the radial planes of FIG. 8, according to an example of the present disclosure; FIG. 9 illustrates horizontal and vertical centerline velocities in the radial plane at positions 1-3 of FIG. 8, according to an example of the present disclosure; FIG. 9 illustrates horizontal and vertical centerline velocities in the radial plane at positions 4-7 of FIG. 8, according to an example of the present disclosure; FIG. 9 illustrates horizontal and vertical centerline velocities in the radial plane at positions 8-11 of FIG. 8, according to an example of the present disclosure; FIG. 9 illustrates horizontal and vertical centerline velocities in the radial plane at positions 12-13 of FIG. 8, according to an example of the present disclosure; FIG. Absorbance vs. 372 nm for four flow rates of 20, 30, 50, 100 ml/min (linear velocities of 1.05E-02, 1.58E-02, 2.63E-02, and 5.26E-02 m/s, respectively) 2 is a graph showing waveform pulse tracer experimental data in time (minutes). Figure 2 is a graph showing dimensionless E-curves of Weave Pulse Tracer experiments at 20, 30, 50, and 100 ml/min.

Like reference numbers identify like elements throughout the specification and drawings.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide explanations of various implementations of the present teachings.

Viral safety is required for protein therapeutics produced within mammalian cells, and viral removal procedures are highly regulated. Viruses can be inactivated by adding compounds or solutions to the process stream. Such compounds or solutions can include at least one of a solvent, a detergent, pasteurization (heat), and pH reduction (acid). Low pH is a highly effective method used in monoclonal antibody purification processes, consistently removing >4 log(10) of large enveloped viruses, including endogenous retroviruses. The American Society for Testing and Materials (ASTM) standards for pH-based retrovirus inactivation processes specify the following low pH virus inactivation conditions: pH ≤ 3.6, ≥ 15°C, specified pH Provides ≧5 log reduction value (LRV) for ≧30 minutes in system-specific buffer at .

Referring to FIGS. 1A-1E, the process stream can be introduced into a continuous flow reactor, such as continuous virus inactivation (CVI) reactor 100, to inactivate viruses. Some exemplary process streams include bioreactor effluent, anion exchange chromatography effluent, cation exchange chromatography effluent, effluent from aqueous two-phase extraction, effluent from precipitation reactions, and membrane filtration steps. effluents, and effluents from ultrafiltration steps.

In one example shown in FIG. 1A, CVI reactor 100 can be configured or designed to minimize and/or reduce pressure drop and axial dispersion. Therefore, the CVI reactor 100 is defined as a flow with a Re number less than 2000, and Re = ρvd/μ, where ρ is the density, v is the average velocity, d is the tube diameter, and μ is the mechanical viscosity. It is possible to operate at low Reynolds (Re) numbers defined as ). For example, the calculation of the Re number can be based on a process stream with a temperature of 25° C., ρ=1000 kg m−3 and μ=8.9E−4 Pa·s. However, laminar flow causes fluid elements in the center of the tube to move faster than elements near the walls, as characterized by a parabolic velocity profile, leading to axial dispersion resulting in a wide residence time distribution (RTD). there is a possibility. As shown in FIGS. 1B, 2A, and 2B, CVI reactor 100 is arranged on a single longitudinal axis LX to reduce and/or at least partially eliminate axial dispersion. can include a flow path or channel 112 having at least two turns or curves 114, such as turns 114A and 114B, that are in different non-parallel planes (eg, plane A and plane B). This particular design can generate secondary flows that promote radial mixing and reduce axial dispersion.

The radius of curvature (ROC) of the turn or curve 114 can be determined as a function of the Dean number (D) and the ratio of the turn length to the toroidal length (L _DT ) (D=Re√(d/2R ) (in the formula, d is the pipe inner diameter and R is the radius of curvature of the flow path), and L _DT =0.322×d _c ^0.31 ×Re ^0.59 ×d _i ^0.76 (in the formula , d _i is the inner diameter and d _c is the coil diameter in meters)).

Reactor Design FIGS. 1A-1E illustrate an exemplary CVI reactor 100. CVI reactor 100 can include a body 102 and a continuous flow reactor tube 110 within body 102.

As shown in FIG. 1A, the CVI reactor 100 can include multiple rows of continuous flow reactor tubes 110, for example, at least five rows of continuous flow reactor tubes 110. In this exemplary CVI reactor 100, the number of turns within each row of continuous flow reactor tubes 110 may depend on the outer diameter and/or inner diameter of the reactor tubes 110. For example, a relatively large diameter reactor tube 110 may include fewer turns than a relatively small diameter reactor tube 110. In one example, if the continuous flow reactor tubes 110 include an ROC from about 0.3 cm or less to about 2 cm or more, such as from about 1.05 cm, each row of continuous flow reactor tubes 110 is for a total of about 320 or more turns. This can include 16 turns. The parameters of CVI reactor 100 may correspond to a Dean number of about 50 or more, such as about 100 or more Dean numbers, such as from about 100 to about 500 Dean numbers.

In one example, prior to introducing the process stream and the at least one virus-inactivating compound or solution into the CVI reactor 100, the combination of the process stream and the virus-inactivating compound or solution has a Reynolds number of about 187 to about 333. and a Dean number of about 105 to about 212.

CVI reactor 100 can include about 50 turns or more, such as about 100 turns or more. For example, a CVI reactor can include approximately 320 turns. 1B and 1C, in order to accommodate approximately 320 turns in a compact design, multiple stacks 180, e.g., two layers 180 to 10 or more layers 180, e.g. In layer 180, channels 112 within CVI reactor 100 can be arranged horizontally. In one example, the flow passages 112 in each layer 180(a)-180(e) within the stack 180 can include from about 28 turns or less to about 68 turns or more. For example, each layer 180(a)-180(e) in stack 180 can include 64 turns. In one example, each layer 180 may be connected to its adjacent underlying layer 180 by a 180° turn 185. In one example where the CVI reactor 100 includes five layers 180, the continuous flow reactor tubes 110 in each of the five layers 180 may be connected to each other by four 180° vertical turns 185.

Referring to FIG. 1B, in one example, each layer 180 within CVI reactor 100 may include a depth L7. Depth L7 may be a distance that can accommodate continuous flow reactor tube 110. At a minimum, depth L7 may be the distance from the center of the first octagonal star in the first layer 180(a) to the center of the second octagonal star in the second layer 180(b). For example, the depth L7 can be defined as a function of the diameter of the continuous reactor tube 110 or the length L3 (shown in FIG. 3C) of the intertwined continuous flow reactor tube 110. In one example, depth L7 ranges from about 6.06 times the diameter size of continuous flow reactor tube 110 (i.e., 6.06*d) to about 7.84 times the diameter size of continuous flow reactor tube 110. (i.e., 7.84*d). For example, L7 can be from about 3.85 cm or less to about 5 cm or more, such as about 4.7 cm. In one example, distance L8 may be from the bottom of the tubular channels 112 in the first layer to the top of the tubular channels 112 in the second layer directly below the first layer. The distance L8 can also be defined as a function of the diameter of the continuous reactor tube 110. In one example, distance L8 ranges from about 0.23 times the size of the diameter of continuous flow reactor tube 110 (i.e., 0.23*d) to about 0.70 times the size of the diameter of continuous flow reactor tube 110 (i.e., 0.23*d) That is, it can be up to 0.7*d). For example, L8 can be from about 0.15 cm (1.5 mm) to about 0.5 cm (5 mm), such as from about 0.425 cm (4.25 mm).

Referring to FIG. 1D, in one example, CVI reactor 100 has body or footprint dimensions L ( 1D) x W (shown as W1 in FIG. 1D) x H (shown as H1 in FIG. 1D), the flow path 112 may be about 442.6 cm to about 7000 cm, such as about 1770.43 cm. length and approximately provide a flow rate of about 300 ml to about 800 ml, such as about 560.68 ml. The body of CVI reactor 100 can include a first side 124 and a second side 126. In one example, first side 124 can include at least one groove or indentation 124A, and second side 126 can include at least one protrusion 126A. The at least one indentation 124A and the at least one protrusion 126A may be arranged such that when two CVI reactors 100 are placed abutting each other, they can be removably secured to each other.

The distance between the center of the reactor entry point and the exit point, designated as H2, can be from about 5 cm or less to about 200 cm or more, such as from about 15 cm to about 25 cm, such as about 23.5 cm. CVI reactor 100 may also include a length from the bottom of the reactor to the handle, designated as H3. The length of H3 may be about 23 cm to about 30 cm, such as about 27.2 cm. In one example, flange 195 can extend from the bottom of CVI reactor 100 from about 0.1 cm to about 1 cm, such as about 0.67 cm. Additionally, flange 195 can include a radius of about 0.3 cm to about 2 cm, such as about 1.1 cm.

In one example, continuous flow reactor tube 110 can include one or more internals. Internals may include, for example, diffusers, catchers, distributors, catalysts, mixers, redistributors, and collectors, to name a few. One or more of these internals can be placed anywhere within continuous flow reactor tube 110 and can be placed in any manner.

In one example, CVI reactor 100 can include sampling ports (not shown) located anywhere throughout the length of continuous flow reactor tube 110. For example, the sampling port can be located approximately halfway between the beginning and end of continuous flow reactor tube 110. extracting a sample of the mixed process stream and the virus-inactivating compound or solution using the sampling port to determine, for example, the pH level or consistency of the mixture, and/or any other properties of the mixture; I can do it. To adjust pH levels, CVI reactor 100 can include an auxiliary input port. An auxiliary input port allows the user to add any necessary additional virus inactivation compounds or solutions or process streams.

In one example, a relatively small or relatively large reactor can be used to accommodate relatively small or relatively large volumes of process streams, and reactor tubes within the relatively small or relatively large reactor. includes an inner diameter substantially similar to reactor 100 and a radius of curvature of 2*.

2A-3D illustrate an exemplary continuous flow reactor tube 110 that can operate at low Re. Continuous flow reactor tube 110 can include a tubular flow path 112 that includes turns or curves 114 and bends 116. At least two of the turns or curves 114 are located on a single longitudinal axis LX, but in different non-parallel planes, such as plane A and plane B. Depending on the number of paths used to form the continuous flow reactor tube 110, the turns may be in two or more different non-parallel planes, such as from about 6 to about 13 different planes, such as 8 different planes. be able to. Furthermore, at least two of the turns are arranged such that the planes corresponding to the at least two turns can intersect each other, as shown for example in FIGS. 2B and 3B. The turns can also form a pattern that may or may not repeat after a predetermined number of turns. For example, a single path can include a pattern 150 that is repeated at least twice, as shown in FIG. 2D, which shows a cross-section of a single path along its longitudinal axis (see also FIG. 2A). Each flow path can include from about 4 turns to about 128 turns or more alternating turns, such as from about 16 to about 32 turns. Each turn 114 can include an angle of about 110° to about 280°, such as about 135° to about 140°. In one example, the first turn can include a smaller angle (such as an angle of about 135°) than the angle of the second turn (such as an angle of about 140°). Further, as shown in FIGS. 2A, 2B, and 3A, each flow path can also include from about 8 to about 64 or more bends 116, such as from about 8 to about 16 bends 116. . Each bend 116 can include an angle of about 15° to less than about 135°, such as an angle of about 30° to about 90°, such as an angle of about 45°. In one example, each pattern 150 may be repeated after about four or more bends, such as after about eight bends.

In another example not shown, the path of continuous flow reactor tube 110 can include two or more different patterns that may or may not repeat. When continuous flow reactor tube 110 includes multiple interwoven flow paths, each path of continuous flow reactor tube 110 can include a substantially similar pattern. Alternatively, or additionally, each path of continuous flow reactor tubes 110 can include a different pattern. Additionally, each path of continuous flow reactor tube 110 may include a similar number of repeating patterns (e.g., two similarly repeating patterns), or may include more or less than two repeating patterns. can. For example, the second path can include two similarly repeating patterns, or it can include three similarly repeating patterns.

As mentioned above, the interwoven tubular channels of the woven design consist of alternating 135°-140° turns with a 45° bend in the center of each turn, as shown in FIG. 2B. The inner diameter of the channel can be from about 0.3 cm or less to about 1 cm or more, such as from about 0.6 cm to about 0.7 cm, such as about 0.635 cm. Additionally, the minimum radius of curvature for a 130-140° turn may be about 0.3 cm to about 2 cm, such as about 1.05 cm, determined for an ID of 0.635 cm.

In one example, as shown in FIG. 2E, the continuous flow reactor tube 110 has a first flow path having a plurality of turns 114 forming a first pattern that can be repeated a predetermined number of times, e.g. and a second flow path that may be straight or include a serpentine pattern between turns of the first flow path. As can be seen in FIG. 2C, the pattern of turns 114 within the first channel forms a top view with an eight-pointed star. As shown in FIG. 3A, when continuous flow reactor tube 110 includes multiple channels, e.g., four channels, each of the four channels is substantially the same and each channel within each channel Turns and patterns may be included that may be interwoven and/or arranged to occupy the spaces formed within the turns. Thus, as shown in FIGS. 2C and 3B, a top view of a continuous flow reactor tube 110 with one or more channels appears substantially like an eight-pointed star.

Referring to FIGS. 2F and 2G, each of the turns 114 in the continuous flow reactor tube 110 can include a vertical L1 center-to-center distance of about 1 cm to about 2 cm, such as about 1.5 cm between turns. Additionally, each of the turns 114 can include a horizontal L2 center-to-center distance of about 1 cm to about 2 cm between turns, such as about 1.63 cm. Further, each of the turns 114 can include an end-to-end distance L3 of about 3 cm to about 4 cm, such as about 3.85 cm. The radius of each turn 114 within continuous flow reactor tube 110 may be substantially constant. For example, referring to FIG. 2G, radii R1 and R2 may be within 0.05 cm or less of each other, such as within about 0.02 cm of each other, to prevent substantial differences in Dean numbers between alternating turns. For example, R1 can be about 1.10 cm and R2 can be about 1.12 cm.

In one example, multiple channels may be interwoven such that multiple turns form a multi-axial three-dimensional channel. Such multi-axis three-dimensional channels can include sheets (as shown in Figures 4A-4C), prisms (not shown), cylinders (as shown in Figure 3A), and cones (not shown). ), and/or to form the overall shape of a sphere (not shown).

In one example, when the channels of the continuous flow reactor tube 110 are interwoven to form a sheet-like structure, the first channel and the second channel form a weft-like pattern, as shown in FIG. 4A. Can include turns. Alternatively, the first channel and the second channel can include turns forming a warp-like pattern, as shown in FIG. 4B. Additionally, in another example, the first flow path can include turns forming a weft-like pattern and the second flow path includes turns forming a warp-like pattern, as shown in FIG. 4C. be able to.

Continuous Flow Reactor Tube Materials and Design Continuous flow reactors according to the invention may be made of any suitable inert material, such as glass, synthetic materials or metal. In another example, continuous flow reactor tube 110 may be made from at least one flexible alloy material and/or memory alloy material. For example, as shown in FIG. 3A, the interwoven channels of continuous flow reactor tube 110 can be made from memory alloy materials or flexible materials. Such materials allow the user of the continuous flow reactor tube 110 to change the shape of the tube and/or manipulate its flow rate as needed without the need to design a new reactor. can do. For example, if the continuous flow reactor tube 110 needs to be heated in a high temperature bath, but the available high temperature bath cannot accommodate the rectangular continuous flow reactor tube 110, the user may The shape of 110 can be modified to be circular to better fit within high temperature baths. Additionally, the use of flexible or memory alloy materials in the continuous flow reactor tube 110 may allow the user to vary the density of turns per square meter of the reactor. This allows a single reactor to be used for multiple purposes. Depending on the purpose of the reactor, the user can straighten some of the turns or add additional turns to the continuous flow reactor tube 110. In one example, the density of 135° to 140° turns per reactor volume can be from about 19.6 turns/m ³ to about 39.2 turns/m ³ .

Details Regarding Interwoven Flow Paths FIGS. 3A-3D illustrate how a continuous flow reactor tube 110 can include a plurality of interwoven flow paths in fluid communication to form a single flow path. A typical design is shown. For example, FIG. 3A shows four paths (pathways 1-4) in fluid communication with each other to form a single flow path 112. This design can allow for a more compact design than a linear pattern of stacking channels side by side by reducing the distance required between the channels and the void space below the channels. FIG. 3A also shows an enlarged view of the four channel weave pattern. In this example, paths 1-4 are connected by curved connections, such as flow path connectors 160, as shown in FIG. 3D, to avoid straight lines in the flow paths.

In one example, as shown in FIGS. 3A and 3D, the flow path connector 160 may be a tube that appears to have two convex end regions and a central concave region, thereby forming an "m" shaped form. Referring to FIG. 3D, the slope between the convex and concave regions can be an angle of about 30 degrees to about 60 degrees, such as an angle of about 45 degrees. Furthermore, the radius R3 of each of the convex regions is about 0.3 cm to about 0.9 cm, such as about 0.65 cm, and the radius R4 of each concave region is about 0.2 cm to about 0.8 cm, such as about 0. .52cm. Further, as can be seen from FIGS. 3B and 3D, the distance L4 from the center of one end of the flow path connector 160 to the center of the second end of the flow path connector 160 is about 2 cm to about 4 cm, for example about 2.96 cm. It can be.

Referring to FIG. 3C, the four channels form the top and bottom views of an octagonal star, as described above. Referring to FIG. 3C, the octagonal star includes at least two vertical parallel tubes, two horizontal parallel tubes, and a flow path connector 160. Each of the turns 114 can include an end-to-end distance L3 of about 3 cm to about 4 cm, such as about 3.85 cm. Further, the distance L5 between each parallel tube is about 1 cm to about 2 cm, for example about 1.65 cm. Further, the distance L6 between the end of the flow path connector 160 and the tube inlet 170 or tube outlet 175 can be about 0.5 cm to about 1.5 cm, such as about 1.1 cm.

Multiple Reactors Connected in Series In one example, in addition to a CVI reactor 100 having multiple layers 180, as shown in FIG. Reactors 100 can be connected in series with each other. This can be achieved with one or more flanged connectors. In one example, at least two tubular CVI reactors 100, such as at least six or more in-line tubular CVI reactors 100, can be connected to each other. In this particular example, the tubular channels 112 at each end of the CVI reactor 100 may partially extend (extension 190) from the CVI reactor 100. Extension 190 can also include a flange 195, as shown in FIG. 1D. Connector 200 can include a horizontal 180° turn and/or be shaped like a "U". One end of the connector can be connected to the tubular channel 112 or flange 195 of the first CVI reactor 100, and the second end of the connector can be connected to the tubular channel 112 or flange 195 of the adjacent in-line tubular CVI reactor 100. It can be connected to flange 195.

Connector 200 connects each tubular channel 112 or It can be connected to flange 195. In one example, a gasket can be placed between the end of tubular channel 112 or flange 195 and each end of connector 200.

Example Example 1
As shown in FIGS. 1A, 1C, and 1D, the curvature of the flow within the CVI reactor 100 created Dean vortices that induced mixing while operating in the laminar flow regime. A 45° bend in the center of the turn further increased mixing by changing the direction of the Dean vortex generated by the turn. Referring to FIG. 6, the image on the left shows the centerline velocity of the centerplane channel, and the image on the right shows the centerline velocity of the 16 135° to 140° turns and 7 45° bends of the woven channel. Show the face. As can be seen in Fig. 6, the centerline velocity profile measured at the center plane of the flow channel, despite operating in the laminar flow regime characterized by a fully developed parabolic velocity profile of the flow. , varied with length. A characteristic parabolic velocity profile was seen at the entrance of the channel shown in Figure 6, where the channel is straight. As the channel transitioned to a woven channel of alternating turns and bends, the centerline velocity profile changed dynamically with length.

To further analyze the velocity profile of the weave design, the axial velocity profile was measured at 45° intervals from the start of the alternating turns, or approximately every 0.9 cm along the flow path, as shown in Figures 7 and 8. and Dean vortices were measured. In FIG. 8, the top image includes a velocity heatmap and an overview of the planes in which axial and radial velocities are measured along the flow path and are numbered 1-13. The inlet velocity was 5.26E-02 m s ^-1 , resulting in a maximum velocity of 1.052E-01 m s ^-1 for fully developed laminar flow. The velocity heatmap ranged from 0 to 1.052E-01 m s ^-1 . The bottom image is an overview of the channel, with velocity contours (top) and radial velocity/Dean vortices (bottom) plotted every 45° from the start of the turn along the channel in 13 planes located at the inlet. , or at intervals of about 0.9 cm.

The average/inlet velocity for each plane in FIG. 8 was predicted to be the maximum velocity of 5.26E-02 m s ^-1 and is shown in the table and graph of FIG. 9. The characteristic value of laminar flow in the pipe at maximum velocity was twice the average velocity (2*va _avg ). Here, our v _avg was 5.26E-02 m s ^-1 and 2*v _avg was 1.052E-01 m s ^-1 . At the inlet, the maximum velocity reached its characteristic maximum before the curvature in the channel. However, in the radial plane within the woven channel, the maximum velocity was lower than the characteristic value. This showed that the flow channels reduced the maximum velocity and therefore the axial dispersion.

For further analysis, both horizontal and vertical centerline velocity profiles of the radial plane of FIG. 8 are shown in FIG. 10. The characteristic symmetric parabolic laminar velocity profile was again seen at the inlet, but as the flow moved through the bend, the profile broadened and became asymmetric.

Example 2
Pulse tracer experiments using CVI woven reactors were performed by first flushing the JIB with Milli-Q water (Barnstead Nanopure Water Purification System, Thermo Scientific, Waltham, MA, USA), followed by 50 mg/ 13ml of ml riboflavin Pulse infusions were given and consisted of a final chase with Milli-Q water via a P-970 system pump on an AKTA Pilot (GE Healthcare, IL, USA). The absorbance of the tracer at the outlet was measured using a UV flow cell on an AKTA Pilot (GE Healthcare) at a wavelength of 372 nm. The absorbance versus time results obtained from pulse tracer experiments at four flow rates of 20, 30, 40, 50, and 100 ml/min are shown in FIG.

Laminar flow occurs at Reynolds numbers (Re) below 2000. The flow Re in a pipe is defined by Equation 1 below, where ρ is the density, v is the average velocity, d is the pipe diameter, and μ is the kinematic viscosity.

For steady motion of an incompressible fluid in a curved pipe, the strength of the secondary flow is the dimensionless It is characterized by the parameter Dean number (D).

The RTD of the reactor is a unitary area under the curve, an E curve, and can be expressed as defined by Equation 3, where C is the concentration of tracer at the outlet and t is time. can.

、及び分散、σ^２によって特徴付けられる。

The axial dispersion is the average residence time defined by Equation 4 and Equation 5, respectively;

, and a variance, σ ² .

Table 1 below shows the Reynolds number (Re), Dean number (D), and dispersion (σ ² ) for the pulse tracer experiment shown above in FIG. These values are important for characterizing the mixing efficiency of our design as relatively low dispersion values, close to the dispersion of the injection pulse, and despite operating in the laminar flow regime with Re < 2000. , indicating that the woven design reactor approaches near-plug flow mixing. If possible, the minimum value of dispersion is 0.1 ^min2 with a maximum flow rate of 100 ml/min.

である）に記載されているように、無次元形式、Ｅ（θ）で表すことができる。分散は、分散を平均滞留時間の二乗値で割ることによって

、無次元時間で表すことができる。図１１の実験データの無次元Ｅ曲線を以下の図１２に示す。無次元ＲＴＤ曲線の１つを中心として対称性が高いほど、反応器はプラグ流反応器としての予備成形に近い。 The E curve is expressed by Equation 6 (where θ is dimensionless time and

), it can be expressed in a dimensionless form, E(θ). The variance is calculated by dividing the variance by the square of the average residence time.

, can be expressed in dimensionless time. A dimensionless E curve of the experimental data of FIG. 11 is shown in FIG. 12 below. The higher the symmetry about one of the dimensionless RTD curves, the closer the reactor is to preforming as a plug flow reactor.

As seen in Figure 12, the dimensionless residence time distribution curve, E(Θ), of 20 ml/min is slightly narrower than the flow rate of 30 ml/min. This is a characteristic of secondary flow within the Dean numerical range of D≦40-60, where the flow is unidirectional. At a higher Dean number D≧60, the Dean vortex becomes stable with a pair of generated vortices.

From the foregoing description, those skilled in the art can understand that the present teachings may be implemented in a variety of forms. Therefore, although these teachings have been described in connection with particular embodiments and examples thereof, the true scope of the present teachings should not be so limited. Various changes and modifications can be made without departing from the scope of the teachings herein.

The scope of this disclosure should be broadly construed. This disclosure is intended to disclose equivalents, means, systems, and methods for accomplishing the devices, activities, and mechanical operations disclosed herein. For each device, article, method, means, mechanical element or mechanism disclosed, this disclosure also encompasses that disclosure and includes any equivalents for implementing the many aspects, mechanisms and devices disclosed herein. It is intended to teach objects, means, systems, and methods. Additionally, the present disclosure relates to coatings and many aspects, features, and elements thereof. Such devices may be dynamic in their use and operation, and this disclosure provides equivalents, means, systems, and methods of use of the devices and/or articles of manufacture, as well as the operations and functions disclosed herein. is intended to include many embodiments thereof consistent with the description and spirit of . The claims of this application should be construed similarly broadly.

The description of the invention in many embodiments herein is merely exemplary in nature and, therefore, variations that do not depart from the gist of the invention are intended to be within the scope of the invention. Such variations are not to be considered a departure from the spirit and scope of the invention.

Claims (15)

comprising a plurality of interwoven flow passages in fluid communication to form a single continuous flow reactor tube having a single flow passage;
each of the plurality of interwoven channels includes a plurality of turns in different non-parallel planes;
each of the plurality of turns is separated from each other by a bend having an angle less than the angle of the plurality of turns;
the plurality of interwoven channels include a plurality of bends, each bend being rotated relative to one another at an angle about a longitudinal axis of the plurality of interwoven channels;
Continuous flow reactor. The plurality of turns includes at least a first pattern and a second pattern different from the first pattern, the first pattern includes a predetermined number of turns, and the second pattern includes a predetermined number of turns. , wherein the predetermined number of turns in the first pattern is the same as or different from the predetermined number of turns in the second pattern. the plurality of turns includes a repeating pattern of turns;
Preferably, the pattern of turns is repeated after eight bends.
A continuous flow reactor according to claim 1 . each of the plurality of turns includes an angle of 100° to 200°;
Preferably, each of the plurality of turns includes an angle of 135° to 140°.
A continuous flow reactor according to claim 1 . 2. The continuous flow reactor of claim 1 , wherein the plurality of turns follow a three-dimensional path including a flow direction that changes by 45 degrees at the center of the turn. Continuous flow reactor according to any one of claims 1 to 5 , wherein the plurality of interwoven channels are made from at least one of a flexible alloy and a memory alloy. Continuous flow reactor according to any one of claims 1 to 6 , wherein the plurality of interwoven channels comprises 19.6 to 39.2 turns per m ³ . A continuous flow reactor according to any one of claims 1 to 7 , wherein the plurality of interwoven flow paths comprises internals. A continuous flow reactor according to any preceding claim, wherein the plurality of interwoven channels comprises a weft-like pattern and a warp -like pattern. Continuous flow reactor according to any one of claims 1 to 9 , wherein the angle around the longitudinal axis of the interwoven channels is between 25 degrees and 60 degrees. at least one flow path on a single longitudinal axis, a plurality of interwoven flow paths in fluid communication to form a single continuous flow reactor tube having a single flow path; A continuous flow reactor comprising a turn of
at least two of the plurality of turns are in different non-parallel planes;
each of the plurality of turns is separated from each other by a bend having an angle less than the angle of the plurality of turns;
at least one channel includes a plurality of bends, each bend being rotated relative to one another at an angle about a longitudinal axis of the plurality of interwoven channels;
Continuous flow reactor. 12. The continuous flow reactor of claim 11 , wherein the plurality of turns includes a first pattern that is repeated a predetermined number of times. The plurality of turns includes at least a first pattern and a second pattern different from the first pattern, the first pattern includes a predetermined number of turns, and the second pattern includes a predetermined number of turns. 12. The continuous flow reactor of claim 11 , wherein the predetermined number of turns in the first pattern is the same as or different from the predetermined number of turns in the second pattern. Preferably , each of the bends includes an angle of less than 135° and each of the plurality of turns includes an angle of between 135° and 140°.
12. A continuous flow reactor according to claim 1 . 12. The continuous flow reactor of claim 11 , wherein the at least one flow path comprises four flow paths interwoven with each other.

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